Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone
The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.
|ISBN||1469-3178 (Electronic) 1469-221X (Linking)|
|Authors||Owen, K. L.; Gearing, L. J.; Zanker, D. J.; Brockwell, N. K.; Khoo, W. H.; Roden, D. L.; Cmero, M.; Mangiola, S.; Hong, M. K.; Spurling, A. J.; McDonald, M.; Chan, C. L.; Pasam, A.; Lyons, R. J.; Duivenvoorden, H. M.; Ryan, A.; Butler, L. M.; Mariadason, J. M.; Giang Phan, T.; Hayes, V. M.; Sandhu, S.; Swarbrick, A.; Corcoran, N. M.; Hertzog, P. J.; Croucher, P. I.; Hovens, C.; Parker, B. S.|
|Responsible Garvan Author||Prof Peter Croucher|
|Publisher Name||EMBO REPORTS|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/32314873|